Dipeptidyl peptidase-IV (DPP-IV) is a serine protease that can rapidly cleave a protein in which an amino acid at the N-terminus of a peptide chain is proline or alanine, is responsible for a metabolic cleavage of some endogenous peptides (such as GLP-1 and GIP) in vivo, and has shown to have a proteolytic activity against a variety of other peptides such as GHRH, NPY, GLP-2 and VIP in vitro. Because of the degradation of DPP-IV, GLP-1 and GIP are rapidly inactivated in vivo, thus inhibiting the activity of DPP-IV would greatly prolong physiological activity duration of GLP-1 and GIP in vivo, which indirectly regulate the insulin secretion and ultimately play a role in controlling a blood glucose level.
As a novel means for treating diabetes, DPP-IV inhibitors can glucose-dependently stimulate insulin secretion, is not prone to have hypoglycemic side effects upon controlling a blood glucose level, and also have some advantages, such as preserving islet β cell function, having few gastrointestinal tract side effects, good tolerance, and the like. DPP-IV inhibitors can be administered orally without the need for injection, and is comparable to existing oral hypoglycemic agents in therapeutic efficacy.
Based on the above features, DPP-IV inhibitors are useful in the treatment and/or prophylaxis of DPP-IV mediated diseases and disorders, such as diabetes, obesity, and the like, particularly type II diabetes.
Currently, eight DPP-IV inhibitors have successfully marketed, which are sitagliptin, vildagliptin, saxagliptin, linagliptin, alogliptin, anagliptin, gemigliptin, and teneligliptin; five DPP-IV inhibitors are in the Phase II/III clinical study; and more DPP-IV inhibitors are in Phase I clinical study and pre-clinical study phase.
Because diabetes is a chronic disease, and patients need lifelong medication, the convenience of medication has a direct impact on whether patients could adhere to treatment. Accordingly, there is an urgent need for novel DPP-IV inhibitors, particularly for long-acting DPP-IV inhibitors.